JPH0517499A - New heptapeptide and insolubilization thereof - Google Patents
New heptapeptide and insolubilization thereofInfo
- Publication number
- JPH0517499A JPH0517499A JP3168208A JP16820891A JPH0517499A JP H0517499 A JPH0517499 A JP H0517499A JP 3168208 A JP3168208 A JP 3168208A JP 16820891 A JP16820891 A JP 16820891A JP H0517499 A JPH0517499 A JP H0517499A
- Authority
- JP
- Japan
- Prior art keywords
- gly
- ala
- boc
- formula
- tyr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000001070 adhesive effect Effects 0.000 claims abstract description 9
- 239000000853 adhesive Substances 0.000 claims abstract description 8
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 10
- 229920001184 polypeptide Polymers 0.000 claims description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
- NIZKGBJVCMRDKO-KWQFWETISA-N Ala-Gly-Tyr Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NIZKGBJVCMRDKO-KWQFWETISA-N 0.000 claims description 4
- 102000004316 Oxidoreductases Human genes 0.000 claims description 2
- 108090000854 Oxidoreductases Proteins 0.000 claims description 2
- 239000003431 cross linking reagent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 102000004169 proteins and genes Human genes 0.000 abstract description 10
- 108090000623 proteins and genes Proteins 0.000 abstract description 10
- -1 t-butyloxycarbonyl Chemical group 0.000 abstract description 6
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 abstract description 4
- 241000237536 Mytilus edulis Species 0.000 abstract description 4
- 235000020638 mussel Nutrition 0.000 abstract description 4
- 239000000227 bioadhesive Substances 0.000 abstract description 3
- 239000011248 coating agent Substances 0.000 abstract description 2
- 238000000576 coating method Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- VLTIIVOWJQDNHG-ZETCQYMHSA-N methyl 2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]acetate Chemical compound COC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C VLTIIVOWJQDNHG-ZETCQYMHSA-N 0.000 abstract description 2
- 230000001464 adherent effect Effects 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 abstract 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000001413 amino acids Chemical group 0.000 description 8
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 238000006116 polymerization reaction Methods 0.000 description 5
- AHMIDUVKSGCHAU-UHFFFAOYSA-N Dopaquinone Natural products OC(=O)C(N)CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-UHFFFAOYSA-N 0.000 description 4
- AHMIDUVKSGCHAU-LURJTMIESA-N L-dopaquinone Chemical compound [O-]C(=O)[C@@H]([NH3+])CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-LURJTMIESA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000015170 shellfish Nutrition 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000237858 Gastropoda Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102000003425 Tyrosinase Human genes 0.000 description 2
- 108060008724 Tyrosinase Proteins 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 238000006068 polycondensation reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- RVLOMLVNNBWRSR-KNIFDHDWSA-N (2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O RVLOMLVNNBWRSR-KNIFDHDWSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 101000611540 Agaricus bisporus Polyphenol oxidase 4 Proteins 0.000 description 1
- 241000238586 Cirripedia Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 241000237502 Ostreidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- IZALUMVGBVKPJD-UHFFFAOYSA-N benzene-1,3-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=C1 IZALUMVGBVKPJD-UHFFFAOYSA-N 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012776 electronic material Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940054441 o-phthalaldehyde Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 235000020636 oyster Nutrition 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000013535 sea water Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Paints Or Removers (AREA)
- Adhesives Or Adhesive Processes (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規ヘプタペプチド及
びその不溶化方法に関する。TECHNICAL FIELD The present invention relates to a novel heptapeptide and a method for insolubilizing the same.
【０００２】[0002]
【従来の技術】海洋中で岩などに付着・接着し生態を維
持しているふじつぼ、い貝、かきなどの無脊椎動物の分
泌するタンパク質は海洋接着タンパクと総称されてい
る。この海洋無脊椎動物の接着作用には長期にわたる観
察・研究史があるが、近年の接着物質の精製法およびア
ミノ酸配列の確立とあいまって、生体適合性のある新素
材つまりバイオ接着剤として期待されている。その具体
的な用途には医学（内科、外科、眼科）、薬学、歯学、
獣医学上での生体関連複合接着剤、水中での汚染防止の
ための表面被覆材料、あるいは導電性電子材料などが挙
げられている。2. Description of the Related Art Proteins secreted by invertebrates such as barnacles, mussels and oysters that adhere to and adhere to rocks in the ocean to maintain their ecology are collectively called marine adhesion proteins. Although the adhesive action of this marine invertebrate has a long history of observation and research, it is expected to be a new biocompatible material, that is, a bioadhesive, in combination with the recent purification of adhesive substances and the establishment of amino acid sequences. ing. Its specific uses include medicine (internal medicine, surgery, ophthalmology), pharmacy, dentistry,
There are mentioned bio-related composite adhesives in veterinary medicine, surface coating materials for preventing contamination in water, and conductive electronic materials.
【０００３】海洋接着タンパク質のうち生化学の立場か
らの分析が最も進んでいるのはむらさきい貝を中心とす
る貝類であり、これら接着タンパク質の製法は始め天然
物抽出・精製から出発したが、次いで高分子合成化学と
遺伝子工学が追随した。初めての高分子合成は本願の発
明者のグループによるむらさきい貝の繰り返しポリペプ
チド（Ａｌａ−Ｌｙａ−Ｐｒｏ−Ｓｅｒ−Ｔｙｒ−４−
Ｈｙｐ−４−Ｈｙｐ−Ｔｈｒ−Ｄｏｐａ−Ｌｙｓ）であ
るが(H.Yamamoto,J.Chem.Soc.,Perkin Trans,I,1987,61
3)、このポリペプチドの９−位のＤｏｐａはペプチド合
成化学の見地からは扱い易いとは言い難いアミノ酸であ
る。Among the marine adhesive proteins, the most advanced analysis from the viewpoint of biochemistry is shellfish centered on the purple shellfish, and the production method of these adhesive proteins started from extraction and purification of natural products. Then, high polymer synthetic chemistry followed by genetic engineering. The first macromolecular synthesis was carried out by the group of the inventors of the present application, which is a repeating polypeptide of Alaska-Lya-Pro-Ser-Tyr-4-.
Hyp-4-Hyp-Thr-Dopa-Lys), but (H. Yamamoto, J. Chem. Soc., Perkin Trans, I, 1987, 61).
3), Dopa at the 9-position of this polypeptide is an amino acid that is difficult to handle from the viewpoint of peptide synthesis chemistry.
【０００４】最近チリ産い貝の接着タンパク質の精製法
が報告された。この繰り返しヘプタペプチドを主とする
接着タンパク質はむらさきい貝の繰り返しデカペプチド
を主とするタンパク質より短いペプチド鎖の繰り返しで
あるため、むらききい貝よりはるかに安価なバイオ接着
剤として有望視されているが、専ら天然物の精製による
試料が供給されている。Recently, a method for purifying the adhesion protein of Chilean mussels has been reported. This repeated heptapeptide-based adhesion protein is a repeat peptide chain that is shorter than the repeated decapeptide-based protein of the Mussel snail, so it is promising as a far cheaper bioadhesive than the Murakiki snail. However, the sample is supplied exclusively from the purification of natural products.
【０００５】[0005]
【発明が解決しようとする課題】本発明は、チリ産い貝
の接着タンパク質に類似する、高分子合成化学により製
造された新規ヘプタペプチド及びその不溶化方法を提供
するものである。DISCLOSURE OF THE INVENTION The present invention provides a novel heptapeptide produced by synthetic polymer chemistry and a method for insolubilizing the same, which is similar to the adhesion protein of Chilean shellfish.
【０００６】[0006]
【課題を解決するための手段】本発明は、アミノ酸配列
が、Ａｌａ−Ｇｌｙ−Ｔｙｒ−Ｇｌｙ−Ｇｌｙ−Ｘ−Ｌ
ｙｓ（ＸはＡｌａ、Ｖａｌ、Ｌｅｕ、Ｉｌｅ又はＰｈ
ｅ）である新規ヘプタペプチド及びそのヘプタペプチド
が繰り返されたポリペプチドに関する。According to the present invention, the amino acid sequence is Ala-Gly-Tyr-Gly-Gly-XL.
ys (X is Ala, Val, Leu, Ile or Ph
e) novel heptapeptides and polypeptides in which the heptapeptides are repeated.
【０００７】図１は、（Ａｌａ−Ｇｌｙ−Ｔｙｒ−Ｇｌ
ｙ−Ｇｌｙ−Ｘ−Ｌｙｓ）n（Ｘ＝Ａｌａ、Ｉｌｅ）の
合成ル−トを示すものである。Ｂｏｃ−Ｔｙｒ（Ｂｚ
ｌ）−ＯＨおよびＢｏｃ−Ｌｙｓ（Ｚ2Ｃｌ）・ｔ−ブ
チルアミンはペプチド研究所より購入した。Ｂｏｃ−Ａ
ｌａおよびＢｏｃ−Ｇｌｙは（Ｂｏｃ）2Ｏを用いて作
った。アミノ酸誘導体およびペプチド誘導体の必要な脱
水縮合にはＤＣＣＩ法を用い、重縮合には活性エステル
法を用いた。すべての反応は薄層クロマト（ＴＬＣ、メ
ルク社シリカゲル６０ＧＦ254）で追跡し、その展開溶
媒はクロロホルム−メタルノール−酢酸（９５：５：
３、Ｖ／Ｖ）などを用いた。中間体はＴＬＣで単−スポ
ットを与えるまで精製し、ＣＨＮ元素分析および旋光度
測定により純度を確認した。FIG. 1 shows (Ala-Gly-Tyr-Gl
1 shows a synthetic route of y-Gly-X-Lys) n (X = Ala, Ile). Boc-Tyr (Bz
l) -OH and Boc-Lys (Z 2 Cl) · t- butylamine was purchased from Peptide Institute. Boc-A
la and Boc-Gly were made using (Boc) 2 O. The DCCI method was used for the necessary dehydration condensation of the amino acid derivative and the peptide derivative, and the active ester method was used for the polycondensation. All reactions were followed by thin layer chromatography (TLC, Merck silica gel 60GF 254 ) and the developing solvent was chloroform-metalnol-acetic acid (95: 5:
3, V / V) or the like was used. The intermediate was purified by TLC to give a single-spot and its purity was confirmed by CHN elemental analysis and optical rotation measurement.
【０００８】Ｂｏｃ−Ｌｙｓ（Ｚ2Ｃｌ）−ＯＮｐ
（１）はＢｏｃ−Ｌｙｓ（Ｚ2Ｃｌ）・ｔ−ブチルアミ
ンとｐ−ニトロフェノールから調製し（収率は９３
％）、４ＭのＨＣｌ／ジオキサン溶液を加えＨＣｌ・Ｌ
ｙｓ（Ｚ2Ｃｌ）−ＯＮｐ（２、収率は８４％）に変え
た。Ｂｏｃ−Ｘ（Ｘ、ＡｌａおよびＩｌｅ）（３）とＤ
ＣＣＩ法でカップリングしＢｏｃ−Ｘ−Ｌｙｓ（Ｚ2Ｃ
ｌ）−ＯＮｐ（５、収率はＡｌａで６３％、Ｉｌｅで６
１％）を合成し、４ＭのＨＣｌ／ジオキサンによりＨＣ
ｌ・Ａｌａ−Ｌｙｓ（Ｚ2Ｃｌ）−ＯＮｐ（６、収率は
Ａｌａで７６％、Ｉｌｅで８２％）に変えた。次いで、
同様な反応でＢｏｃ−Ｇｌｙとカップリングし、Ｂｏｃ
−Ｇｌｙ−Ｘ−Ｌｙｓ（Ｚ2Ｃｌ）−ＯＮｐ（７、収率
はＡｌａで６９％、Ｉｌｅで７３％）を経てＣ−端側ト
リペプチドＨＣｌ・Ｇｌｙ−Ｘ−Ｌｙｓ（Ｚ2Ｃｌ）−
ＯＮｐ（８、収率はＡｌａで６８％、Ｉｌｅで７４％）
を得た。Boc-Lys (Z 2 Cl) -ONp
(1) was prepared from Boc-Lys (Z 2 Cl) .t-butylamine and p-nitrophenol (yield 93
%) 4M HCl / dioxane solution was added
It was changed to ys (Z 2 Cl) -ONp (2, yield 84%). Boc-X (X, Ala and Ile) (3) and D
Boc-X-Lys (Z 2 C was coupled by the CCI method.
l) -ONp (5, yield 63% for Ala, 6 for Ile
1%) and HC with 4M HCl / dioxane
l · Ala-Lys (Z 2 Cl) -ONp (6, yield 76% for Ala, 82% for Ile). Then
In a similar reaction, coupled with Boc-Gly, Boc
-Gly-X-Lys (Z 2 Cl) -ONp (7, yield 69% in Ala, Ile 73 percent) through the C- terminal side tripeptide HCl · Gly-X-Lys ( Z 2 Cl) -
ONp (8, yield 68% for Ala, 74% for Ile)
Got
【０００９】通常の塩酸ガス法で作ったＨＣｌ・Ｈ−Ｇ
ｌｙ−ＯＭｅ（４）とＢｏｃ−ＡｌａをＤＣＣＩ法でカ
ップリングしＢｏｃ−Ａｌａ−Ｇｌｙ−ＯＭｅ（９、収
率は７８％）を得、１ＭのＮａＯＨを用いてけん化しＢ
ｏｃ−Ａｌａ−Ｇｌｙ（１０、収率は７８％）を得た。
Ｂｏｃ−Ｔｙｒ（Ｂｚｌ）−Ｇｌｙ−ＯＭｅ（１１）は
Ｂｏｃ−Ｔｙｒ（Ｂｚｌ）と化合物４をＤＣＣＩ法によ
りカップリングし（収率は８１％）、ついでＨＣｌ・Ｔ
ｙｒ（Ｂｚｌ）−Ｇｌｙ−ＯＭｅ（１２、収率は９１
％）に変えた。化合物と１０と１２をクロロホルム−酢
酸エチル中でカップリングしＢｏｃ−Ａｌａ−Ｇｌｙ−
Ｔｙｒ（Ｂｚｌ）−Ｇｌｙ−ＯＭｅ（１３、収率は６７
％）を得た。けん化によりＢｏｃ−Ａｌａ−Ｇｌｙ−Ｔ
ｙｒ（Ｂｚｌ）−Ｇｌｙ（１４、収率は９０％）に変え
た。HCl / HG prepared by the usual hydrochloric acid gas method
Ly-OMe (4) and Boc-Ala were coupled by the DCCI method to obtain Boc-Ala-Gly-OMe (9, yield 78%), saponified with 1M NaOH B
oc-Ala-Gly (10, yield 78%) was obtained.
Boc-Tyr (Bzl) -Gly-OMe (11) couples Boc-Tyr (Bzl) with compound 4 by the DCCI method (yield 81%), and then HCl.T.
yr (Bzl) -Gly-OMe (12, yield 91
%). Compounds 10 and 12 were coupled in chloroform-ethyl acetate and Boc-Ala-Gly-
Tyr (Bzl) -Gly-OMe (13, yield 67
%) Was obtained. Boc-Ala-Gly-T by saponification
It was changed to yr (Bzl) -Gly (14, yield 90%).
【００１０】Ｂｏｃ−Ａｌａ−Ｇｌｙ−Ｔｙｒ（Ｂｚ
ｌ）−Ｇｌｙ−Ｇｌｙ−Ｘ−Ｌｙｓ（Ｚ2Ｃｌ）−ＯＮ
ｐ（１５）はクロロホルム中で化合物１４と化合物８を
カップリングして得（収率はＡｌａで６８％、Ｉｌｅで
５９％）、次いでＨＣｌ・Ａｌａ−Ｇｌｙ−Ｔｙｒ（Ｂ
ｚｌ）−Ｇｌｙ−Ｇｌｙ−Ａｌａ−Ｌｙｓ（Ｚ2Ｃｌ）
−ＯＮｐ（１６）に変えた（収率はＡｌａで６７％、Ｉ
ｌｅで６７％）。Boc-Ala-Gly-Tyr (Bz
l) -Gly-Gly-X- Lys (Z 2 Cl) -ON
p (15) was obtained by coupling compound 14 and compound 8 in chloroform (yield 68% for Ala, 59% for Ile), then HCl.Ala-Gly-Tyr (B
zl) -Gly-Gly-Ala-Lys (Z 2 Cl)
-ONp (16) was changed (yield 67% in Ala, I
67% in le).
【００１１】重縮合はヘプタペプチド活性エステル塩酸
塩（１６）を精製ジメチルホルムアミドに溶かし、１．
１等量のトリエチルアミンを加え１０日間放置した。洗
浄および精製後、ポリ〔Ａｌａ−Ｇｌｙ−Ｔｙｒ（Ｂｚ
ｌ）−Ｇｌｙ−Ｇｌｙ−Ａｌａ−Ｌｙｓ（Ｚ2Ｃｌ）〕
（１７−Ａｌａ、収率は８５％、ＣＨＮ：分析値・Ｃ５
８．１％、Ｈ６．０％、Ｎ１２．７％、理論値（Ｃ42Ｈ
51Ｎ8Ｏ10Ｃｌ）・Ｃ５８．４％、Ｈ６．０％、Ｎ１
３．０％）およびポリ〔Ａｌａ−Ｇｌｙ−Ｔｙｒ（Ｂｚ
ｌ）−Ｇｌｙ−Ｇｌｙ−Ｉｌｅ−Ｌｙｓ（Ｚ2Ｃｌ）〕
（１７−Ｉｌａ、収率は７８％、ＣＨＮ：分析値・Ｃ５
９．４％、Ｈ６．７％、Ｎ１２．６％、理論値（Ｃ45Ｈ
57Ｎ8Ｏ10Ｃｌ）・Ｃ５９．７％、Ｈ６．４％、Ｎ１
２．４％）が得られた。保護ポリヘプタペプチド（１
７）をトリフロロ酢酸に溶かし、３．１ＭのＨＢｒ／Ａ
ｃＯＨとチオアニソールを加え、５０℃で１０時間、次
いで室温にて５日間撹拌し側鎖保護基を完全に除去し、
ポリ〔Ａｌａ−Ｇｌｙ−Ｔｙｒ−Ｇｌｙ−Ｇｌｙ−Ａｌ
ａ−Ｌｙｓ（ＨＢｒ）〕・８Ｈ2Ｏ（１８−Ａｌａ、収
量０．５５ｇ、収率９５％）およびポリ〔Ａｌａ−Ｇｌ
ｙ−Ｔｙｒ−Ｇｌｙ−Ｇｌｙ−Ｉｌｅ−Ｌｙｓ（ＨＢ
ｒ）〕・１０Ｈ2Ｏ（１８−Ｉｌｅ、収量０．５３ｇ、
収率８８％）を得た。For polycondensation, heptapeptide active ester hydrochloride (16) was dissolved in purified dimethylformamide, and 1.
1 equivalent of triethylamine was added and left for 10 days. After washing and purification, poly [Ala-Gly-Tyr (Bz
l) -Gly-Gly-Ala-Lys (Z 2 Cl)]
(17-Ala, yield 85%, CHN: analytical value, C5
8.1%, H6.0%, N12.7%, theoretical value (C 42 H
51 N 8 O 10 Cl) ・ C58.4%, H6.0%, N1
3.0%) and poly [Ala-Gly-Tyr (Bz
l) -Gly-Gly-Ile-Lys (Z 2 Cl)]
(17-Ila, yield 78%, CHN: analytical value, C5
9.4%, H6.7%, N12.6%, theoretical value (C 45 H
57 N 8 O 10 Cl) .C59.7%, H6.4%, N1
2.4%) was obtained. Protected polyheptapeptide (1
7) was dissolved in trifluoroacetic acid to obtain 3.1 M HBr / A
cOH and thioanisole were added, and the mixture was stirred at 50 ° C. for 10 hours and then at room temperature for 5 days to completely remove the side chain protecting group,
Poly [Ala-Gly-Tyr-Gly-Gly-Al
a-Lys (HBr)]. 8H 2 O (18-Ala, yield 0.55 g, yield 95%) and poly [Ala-Gl.
y-Tyr-Gly-Gly-Ile-Lys (HB
r)] · 10H 2 O (18-Ile , yield 0.53g,
Yield 88%) was obtained.
【００１２】図２は、（Ａｌａ−Ｇｌｙ−Ｔｙｒ−Ｇｌ
ｙ−Ｇｌｙ−Ｘ−Ｌｙｓ）n （Ｘ＝Ｐｈｅ、Ｌｅｕ、Ｖ
ａｌ）の合成ル−トを示すものである。この場合、Ｎ末
端保護差としてＢｏｃ基よりも酸に敏感で、２Ｍ塩化水
素処理においてＢｏｃ基よりも７０倍も切断の容易なＯ
−ニトロフェニルスルフェニルを使用した。これ以外は
図１の合成ル−トと同様にして（Ａｌａ−Ｇｌｙ−Ｔｙ
ｒ−Ｇｌｙ−Ｇｌｙ−Ｘ−Ｌｙｓ）n （Ｘ＝Ｐｈｅ、Ｌ
ｅｕ、Ｖａｌ）を合成した。FIG. 2 shows (Ala-Gly-Tyr-Gl
y-Gly-X-Lys) n (X = Phe, Leu, V
3 shows a synthetic route of al). In this case, as the difference in N-terminal protection, O was more sensitive to acid than the Boc group, and easily cleaved 70 times more easily than the Boc group in 2M hydrogen chloride treatment.
-Nitrophenylsulfenyl was used. Except for this, the synthesis route of FIG. 1 is the same as (Ala-Gly-Ty).
r-Gly-Gly-X-Lys) n (X = Phe, L
eu, Val) was synthesized.
【００１３】合成した側鎖保護ポリペプチド（１７、３
５）の平均重合度をその固有粘度から求めた。このとき
用いた粘度式は以下の三式である
２５℃、溶媒ＤＡＣSynthesized side chain protected polypeptides (17, 3
The average degree of polymerization of 5) was determined from its intrinsic viscosity. The viscosity formulas used at this time are the following three formulas: 25 ° C., solvent DAC
【数１】 [Equation 1]
【数２】
ｌｏｇＤＰ＝１．４７×ｌｏｇ〔η〕＋２．９９
平均重合度、平均アミノ酸重合度、繰り返し数は次の通
りである。
Ｘ 平均重合度 平均アミノ酸重合度 繰り返し数
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Ａｌａ 約２０８００ １６８ ２４
Ｉｌｅ 約１５４００ １１９ １７
Ｐｈｅ 約１１６００ １１９ １７
Ｌｅｕ 約１４９００ １６１ ２３
Ｖａｌ 約１６５００ １８２ ２６ [Equation 2] logDP = 1.47 × log [η] +2.99 The average degree of polymerization, the average degree of amino acid polymerization, and the number of repetitions are as follows. X Average Degree of Polymerization Average Amino Acid Degree of Polymerization Repeat Number ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Ala Approx. 20800 168 24 Ile Approx. 15400 119 17 Phe About 11600 119 17 Leu About 14900 161 23 Val About 16500 182 26
【００１４】化合物１８、化合物３６のアミノ酸分析結
果は次の通りである。
Ｘ＝Ａｌａ：Ａｌａ2.10、Ｇｌｙ2.81、Ｔｙｒ1.00、Ｌｙｓ1.11
Ｘ＝Ｉｌｅ：Ａｌａ0.96、Ｇｌｙ2.99、Ｔｙｒ1.00、Ｉｌｅ1.15、Ｌｙｓ1.14
Ｘ＝Ｐｈｅ：Ａｌａ1.13、Ｇｌｙ2.91、Ｔｙｒ1.00、Ｐｈｅ1.00、Ｌｙｓ1.02
Ｘ＝Ｌｅｕ：Ａｌａ1.15、Ｇｌｙ3.04、Ｔｙｒ1.00、Ｌｅｕ1.04、Ｌｙｓ1.05
Ｘ＝Ｖａｌ：Ａｌａ1.10、Ｇｌｙ3.09、Ｔｙｒ1.00、Ｖａｌ0.94、Ｌｙｓ0.95
The amino acid analysis results of compound 18 and compound 36 are as follows. X = Ala: Ala 2.10 , Gly 2.81 , Tyr 1.00 , Lys 1.11 X = Ile: Ala 0.96 , Gly 2.99 , Tyr 1.00 , Ile 1.15 , Lys 1.14 X = Phe: Ala 1.13 , Gly 2.91 , Tyr 1.00 , Pyr 1.00 , Pyr 1.00 , Pyr 1.00 . 1.02 X = Leu: Ala 1.15 , Gly 3.04 , Tyr 1.00 , Leu 1.04 , Lys 1.05 X = Val: Ala 1.10 , Gly 3.09 , Tyr 1.00 , Val 0.94 , Lys 0.95
【００１５】ＸがＩｌｅの化合物１８（１．７ｍｇ）を
人工海水に溶かし（ｐＨ７）、酸化酵素チロシナーゼ４
２ｕｎｉｔを加え２５℃における吸収スペクトルの変化
を測定した。４〜５分後にＴｙｒからＤｏｐａへの転換
が起こり始め一夜経つとＴｙｒの吸収極大は消失し、Ｄ
ｏｐａおよびＤｏｐａキノンの吸収極大が観察され、そ
の後も時間と共に光学濃度は増し続けＤｏｐａキノンを
経ての不溶化の傾向が認められる。図３は、酵素により
Ｔｙｒ→Ｄｏｐａ→Ｄｏｐａキノンと変化したときのポ
リペプチドのスペクトル変化を示すものであり、図３に
示すように、ＴｙｒからＤｏｐａの変換はＤｏｐａの吸
収極大波長２８３ｍと連続酸化で生成するＤｏｐａキノ
ンの吸収極大波長３４０−３５０ｍの出現で確認され
る。図３でＡは酸化酵素チロシナ−ゼを加えない場合、
Ｂは酸化酵素チロシナ−ゼを加えた場合のグラフであ
る。Compound 18 (1.7 mg) in which X is Ile was dissolved in artificial seawater (pH 7), and the oxidase tyrosinase 4 was added.
2 unit was added to measure the change in absorption spectrum at 25 ° C. After 4 to 5 minutes, the conversion of Tyr to Dopa began to occur, and the absorption maximum of Tyr disappeared overnight, and D
The absorption maxima of opa and Dopaquinone are observed, and thereafter, the optical density continues to increase with time, and a tendency of insolubilization via Dopaquinone is observed. FIG. 3 shows the spectrum change of the polypeptide when the enzyme changes Tyr → Dopa → Dopa quinone. As shown in FIG. 3, the conversion of Tyr to Dopa is the maximum absorption wavelength of Dopa of 283 m and continuous oxidation. It is confirmed by the appearance of the absorption maximum wavelength of 340-350 m of the Dopaquinone produced in Step 1. In FIG. 3, A is the case where the oxidative enzyme tyrosinase was not added,
B is a graph when oxidase tyrosinase was added.
【００１６】本発明のペプチドを不溶化させるには、酸
化酵素の他に、グルタルアルデヒド、グリオキザ−ル、
ｏ−フタルアルデヒド、ｍ−フタルアルデヒド、ｐ−フ
タルアルデヒド等の架橋剤が使用される。To insolubilize the peptide of the present invention, in addition to oxidase, glutaraldehyde, glyoxal,
Crosslinking agents such as o-phthalaldehyde, m-phthalaldehyde, p-phthalaldehyde are used.
【００１７】[0017]
【発明の効果】チリ産い貝の接着タンパク質のアミノ酸
シークエンスは（Ａｌａ−Ｇｌｙ−Ｄｏｐａ−Ｇｌｙ−
Ｇｌｙ−Ｘ−Ｌｙｓ）n であり６−位のＸは疏水性アミ
ノ酸（Ａｌａ、Ｖａｌ、Ｌｅｕ、Ｉｌｅ、Ｐｈｅ）であ
る。一般にＤｏｐａを組み込んだペプチド合成は相当困
難であり、ＤｏｐａをＴｙｒに読み替えられるならその
難度は軽減する。本発明のペプチドは、水系で迅速、簡
便に不溶化、接着性をもたせることが可能で、例えば生
体適合性のある接着剤として使用される。具体的な用途
としては医学（内科、外科、眼科）、薬学、歯学、獣医
学上での生体関連複合接着剤などがある。EFFECTS OF THE INVENTION The amino acid sequence of the adhesion protein of Chilean mollusks is (Ala-Gly-Dopa-Gly-
Gly-X-Lys) n and X at the 6-position is a hydrophobic amino acid (Ala, Val, Leu, Ile, Phe). Generally, peptide synthesis incorporating Dopa is considerably difficult, and if Dopa can be read as Tyr, the degree of difficulty is reduced. INDUSTRIAL APPLICABILITY The peptide of the present invention can be insolubilized rapidly and simply in water and can have adhesiveness, and is used as, for example, a biocompatible adhesive. Specific applications include biomedical composite adhesives in medicine (internal medicine, surgery, ophthalmology), pharmacy, dentistry, and veterinary medicine.
【図１】合成ル−トを示すフロ−チャ−ト。FIG. 1 is a flowchart showing a synthetic route.
【図２】合成ル−トを示すフロ−チャ−ト。FIG. 2 is a flowchart showing a synthetic route.
【図３】ポリペプチドのスペクトル変化を示すグラフ。FIG. 3 is a graph showing a spectrum change of a polypeptide.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０９Ｄ 5/14 ＰＱＪ 6904−4Ｊ ＰＱＬ 6904−4Ｊ Ｃ０９Ｊ 189/00 ＪＡＪ 6770−4Ｊ Ｃ０７Ｋ 99:00 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical display location C09D 5/14 PQJ 6904-4J PQL 6904-4J C09J 189/00 JAJ 6770-4J C07K 99:00
Claims (4)
−Ｇｌｙ−Ｇｌｙ−Ｘ−Ｌｙｓ（ＸはＡｌａ、Ｖａｌ、
Ｌｅｕ、Ｉｌｅ又はＰｈｅ）である新規ヘプタペプチ
ド。1. An amino acid sequence of Ala-Gly-Tyr.
-Gly-Gly-X-Lys (X is Ala, Val,
A novel heptapeptide which is Leu, Ile or Phe).
ポリペプチド。2. A polypeptide in which the heptapeptide of claim 1 is repeated.
／又は架橋剤を添加することを特徴とするペプチドの不
溶化方法。3. A method for insolubilizing a peptide, which comprises adding an oxidase and / or a crosslinking agent to the peptide according to claim 1 or 2.
む接着剤。4. An adhesive containing the peptide insolubilized according to claim 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3168208A JPH0517499A (en) | 1991-07-09 | 1991-07-09 | New heptapeptide and insolubilization thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3168208A JPH0517499A (en) | 1991-07-09 | 1991-07-09 | New heptapeptide and insolubilization thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0517499A true JPH0517499A (en) | 1993-01-26 |
Family
ID=15863796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3168208A Pending JPH0517499A (en) | 1991-07-09 | 1991-07-09 | New heptapeptide and insolubilization thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0517499A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004082762A1 (en) | 2003-03-17 | 2004-09-30 | Medi-Physics, Inc. | Products and methods for brachytherapy |
| WO2018214619A1 (en) * | 2017-05-26 | 2018-11-29 | 中国船舶重工集团公司第七二五研究所 | Controlled release material for fouling organism-sensitive response anti-fouling agent, and method for manufacturing same |
-
1991
- 1991-07-09 JP JP3168208A patent/JPH0517499A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004082762A1 (en) | 2003-03-17 | 2004-09-30 | Medi-Physics, Inc. | Products and methods for brachytherapy |
| WO2018214619A1 (en) * | 2017-05-26 | 2018-11-29 | 中国船舶重工集团公司第七二五研究所 | Controlled release material for fouling organism-sensitive response anti-fouling agent, and method for manufacturing same |
| US11000034B2 (en) | 2017-05-26 | 2021-05-11 | Luoyang Ship Material Research Institute | Controlled-release material for antifouling agent sensitive and response to fouling organisms and preparation method thereof |
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